Dermal Absorption
Total Page：16
File Type：pdf, Size：1020Kb
This report contains the collective views of an international group of experts and does not necessarily represent the decisions or the stated policy of the United Nations Environment Programme, the International Labour Organization or the World Health Organization. Environmental Health Criteria 235 DERMAL ABSORPTION First draft prepared by Drs Janet Kielhorn, Stephanie Melching- Kollmuß, and Inge Mangelsdorf, Fraunhofer Institute of Toxicology and Experimental Medicine, Hanover, Germany Published under the joint sponsorship of the United Nations Environment Programme, the International Labour Organization and the World Health Organization, and produced within the framework of the Inter-Organization Programme for the Sound Management of Chemicals. The International Programme on Chemical Safety (IPCS), established in 1980, is a joint venture of the United Nations Environment Programme (UNEP), the International Labour Organization (ILO) and the World Health Organization (WHO). The overall objec- tives of the IPCS are to establish the scientific basis for assessment of the risk to human health and the environment from exposure to chemicals, through international peer review processes, as a prerequisite for the promotion of chemical safety, and to provide technical assistance in strengthening national capacities for the sound management of chemicals. The Inter-Organization Programme for the Sound Management of Chemicals (IOMC) was established in 1995 by UNEP, ILO, the Food and Agriculture Organization of the United Nations, WHO, the United Nations Industrial Development Organization, the United Nations Institute for Training and Research and the Organisation for Economic Co-operation and Development (Participating Organizations), following recommendations made by the 1992 UN Conference on Environment and Development to strengthen coop- eration and increase coordination in the field of chemical safety. The purpose of the IOMC is to promote coordination of the policies and activities pursued by the Participating Organizations, jointly or separately, to achieve the sound management of chemicals in relation to human health and the environment. WHO Library Cataloguing-in-Publication Data Dermal absorption. (Environmental health criteria ; 235) 1.Skin absorption. 2.Risk assessment. 3.Environmental exposure. I.World Health Organization. II.International Programme on Chemical Safety. III.Series. ISBN 92 4 157235 3 (NLM classification: WR 102) ISBN 978 92 4 157235 4 ISSN 0250-863X © World Health Organization 2006 All rights reserved. Publications of the World Health Organization can be obtained from WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; e-mail: [email protected]). Requests for permission to reproduce or translate WHO publications – whether for sale or for noncommercial distribution – should be addressed to WHO Press, at the above address (fax: +41 22 791 4806; e-mail: [email protected]). The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by the World Health Organization to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable for damages arising from its use. This document was technically and linguistically edited by Marla Sheffer, Ottawa, Canada, and printed by Wissenchaftliche Verlagsgesellschaft mbH, Stuttgart, Germany. CONTENTS ENVIRONMENTAL HEALTH CRITERIA FOR DERMAL ABSORPTION PREAMBLE x ACRONYMS AND ABBREVIATIONS xvii 1. SUMMARY 1 2. INTRODUCTION AND DEFINITIONS 6 2.1 Scope of the document 6 2.2 Definition of dermal absorption 8 2.3 Factors influencing dermal absorption 8 3. SKIN STRUCTURE AND FUNCTION 10 3.1 Functions of the skin 10 3.1.1 Barrier function 10 3.1.2 Temperature control 11 3.1.3 Defence and repair 11 3.2 Skin structure 12 3.2.1 Epidermis 12 3.2.2 Dermis 16 3.2.3 Skin appendages 16 3.3 The transport of chemicals through the skin 17 3.4 Variability in skin permeability 17 3.4.1 Species 17 3.4.2 Age, sex, and race 18 3.4.3 Anatomical site 19 3.4.4 Skin condition 19 3.4.5 Temperature and blood flow rate 19 3.4.6 Hydration 20 3.5 Reservoir effects 20 iii EHC 235: Dermal Absorption 4. SKIN TRANSPORT MECHANISMS AND THEORETICAL CONCEPTS 23 4.1 Transport through the skin 23 4.2 Theoretical aspects of diffusion 23 4.3 Physicochemical factors affecting skin permeation 26 4.3.1 Physical state 27 4.3.2 Molecular size/molecular weight 27 4.3.3 Maximum flux 28 4.3.4 Ionization 28 4.3.5 Binding properties 29 4.4 Concepts of finite and infinite dose 29 5. METABOLISM IN THE SKIN 32 5.1 The drug-metabolizing systems of the skin 33 5.2 Methodology for evaluating skin metabolism in in vitro systems 35 5.3 Effects of skin metabolism 35 5.4 Importance of metabolism for percutaneous absorption 36 6. IN VITRO TESTS FOR DERMAL ABSORPTION 38 6.1 Test guidelines 38 6.2 Principles of the standard in vitro tests using skin samples 39 6.2.1 Test chambers 39 6.2.1.1 Static diffusion cells 40 6.2.1.2 Flow-through cells 40 6.2.1.3 Comparison of different in vitro cell systems 42 6.2.2 Finite/infinite dosing 43 6.2.3 Skin preparations 44 6.2.3.1 Choice of skin 44 6.2.3.2 Preparation of tissue samples 45 6.2.3.3 Checking of barrier integrity 46 6.2.4 Application of test substance 47 6.2.4.1 Test substance 47 6.2.4.2 Vehicle 48 6.2.4.3 Receptor fluid 48 6.2.4.4 Application dose levels 50 iv Contents 6.2.5 Duration of exposure and sampling time 50 6.2.6 Evaluation of the results 50 6.2.6.1 Dermal absorption results after finite dosing 51 6.2.6.2 Dermal absorption results after infinite dosing 52 6.3 Other in vitro methods 52 6.3.1 Artificial skin 52 6.3.2 Tape-stripping technique in vitro 52 6.4 Examination of skin reservoir characteristics 53 6.5 Experimental factors affecting dermal absorption in vitro 54 6.5.1 Species differences 54 6.5.2 Temperature 55 6.5.3 Occlusion 56 6.5.4 Thickness of skin 56 6.5.5 Further observations on application vehicle effects 58 7. IN VIVO TESTS FOR DERMAL ABSORPTION 60 7.1 Laboratory animal studies 60 7.1.1 Test guidelines for laboratory animal studies 61 7.1.2 Principles of the standard in vivo tests 61 7.1.2.1 Preparation of the application site 62 7.1.2.2 Dose levels 62 7.1.2.3 Application of the test substance to the skin 62 7.1.2.4 Duration of exposure 63 7.1.2.5 Sacrifice and time of termination 63 7.1.2.6 Evaluation of the results 64 7.2 Studies with human volunteers 65 7.2.1 Assessment using plasma, excreta, and breath analysis 66 7.2.1.1 Methodology 66 7.2.1.2 Examples of in vivo human volunteer studies 66 7.2.1.3 Biomonitoring of occupational exposure 67 7.2.2 Cutaneous microdialysis 68 7.2.3 Tape stripping 70 v EHC 235: Dermal Absorption 7.3 Other methods 73 7.3.1 Whole-body autoradiography 73 7.3.2 Skin biopsy 73 7.4 Factors affecting dermal absorption in vivo 74 7.4.1 Species, strain, and sex 74 7.4.2 Age 75 7.4.3 Anatomical site 75 7.4.4 Type of application and vehicle 77 7.4.5 Temperature and humidity conditions 78 8. COMPARATIVE STUDIES 79 8.1 Comparison between in vitro and in vivo skin absorption results 79 8.2 Inter- and intralaboratory variation in in vitro percutaneous absorption methodology 84 9. DATA COLLECTIONS 86 9.1 Data sets from homologous or closely related molecules 86 9.2 Flynn data set 87 9.3 Expanded permeability coefficient data sets 88 9.4 EDETOX database 88 9.5 Maximum flux databases 89 10. ESTIMATION/PREDICTION OF DERMAL PENETRATION 90 10.1 QSAR analysis 91 10.1.1 Prerequisites for QSPeR analysis 91 10.1.2 Historical overview 92 10.1.2.1 QSPeRs for skin permeability prior to the 1990s 92 10.1.2.2 The Flynn (1990) data set and subsequent analyses 93 10.1.2.3 Other data sets 97 10.1.3 Other approaches to QSPeR 97 10.1.4 Variability of data and its relevance for QSPeRs 98 10.1.5 Statistical analysis (linear vs non- linear) methods 98 vi Contents 10.1.6 Selection of chemicals for further tests on dermal penetration 98 10.1.7 Applicability domain for QSPeR 99 10.1.8 Maximum fluxes 99 10.1.9 Rules as an alternative to QSPeRs 100 10.2 Mathematical modelling 100 10.3 Mathematical pharmacokinetic models of percutaneous penetration 103 11.